Effect of physical aging on nucleation of amorphous indomethacin.

Differential scanning calorimetry has been used to study glassy indomethacin aged at 0 and -10 degrees C for periods of time up to 109 and 210 days, respectively. The results demonstrate the emergence of a small melting peak of the alpha-polymorph after aging for 69 days at 0 degrees C and for 147 days at -10 degrees C (i.e., approximately 55 degrees C below the glass-transition temperature) that provides evidence of nucleation occurring in the temperature region of the beta-relaxation. The evolution of an endothermic recovery peak temperature features a plateau at longer annealing times that suggests that the glass has made significant progress toward reaching the supercooled liquid state. It has been found that the melting peaks become detectable after the recovery peak has reached the plateau. The results highlight the importance of studying physical aging in the temperature region of the beta-relaxation as a means of evaluating the physical stability of amorphous pharmaceutical materials.